Inhibition of bradykinin B2 receptor preserves microcirculation in experimental pancreatitis in rats.
The effect of B2 receptor bradykinin antagonist icatibant on postcapillary leukostasis, microcirculatory stasis, and tissue necrosis was studied in acute pancreatitis. In rats, pancreatitis was induced by intraductal injection of sodium taurocholate (ST), intravenous caerulein and intraductal infusion of glucodeoxycholic acid (GDOC), or intravenous caerulein infusion alone. Intravital pancreatic microcirculation was observed. Icatibant or vehicle was given 30 min before induction of pancreatitis. In ST pancreatitis, the number of perfused capillaries increased in icatibant-pretreated rats (77% vs. 0% for controls, P < 0.001). Capillary flow was preserved in icatibant-treated rats; total stasis was observed in controls. Mean venular leukocyte adherence decreased in icatibant-treated rats (26% vs. 74% for controls, P < 0.001), and median histopathologic score was reduced (icatibant vs. controls, 5.0 vs. 12 points, respectively; P < 0.01). Kinase II inhibitor captopril or exogenous bradykinin in addition to an otherwise effective dosage of icatibant resulted in microcirculatory stasis, extensive venular leukocyte adherence, and severe histological damage. With a 100 times greater icatibant dosage, this adverse effect was compensated. The beneficial effects of icatibant were also observed in intermediate pancreatitis (caerulein + GDOC). In ST and intermediate pancreatitis, icatibant preserved microcirculation, reduced venular leukocyte adherence, and prevented pancreatic tissue damage. B2 receptor bradykinin-mediated postcapillary leukostasis plays an important role in the pathogenesis of severe forms of acute pancreatitis.
Bloechle
C
C
Department of Surgery, University of Hamburg, Germany.
Kusterer
K
K
Kuehn
R M
RM
Schneider
C
C
Knoefel
W T
WT
Izbicki
J R
JR
D000208:Acute Disease; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002196:Capillaries / Q000503:physiopathology; D002448:Cell Adhesion; D002108:Ceruletide; D004487:Edema; D005260:Female; D006470:Hemorrhage; D007962:Leukocytes / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D010179:Pancreas / Q000098:blood supply*; D010195:Pancreatitis / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D043782:Receptor, Bradykinin B2; D012039:Regional Blood Flow; D013656:Taurocholic Acid; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014699:Venules / Q000187:drug effects / Q000503:physiopathology
D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D013656:Taurocholic Acid; C065679:icatibant; D002108:Ceruletide; D001920:Bradykinin